Breast cancer is the most frequent malignant tumor of women in western countries. The prognosis of early breast carcinoma is influenced by several clinical and biological parameters. Among these, signs of early dissemination such as presence of tumor cell in the regional lymph nodes, and possibly in the bone marrow, are well established adverse prognostic factors (Solomayer et al., 2001, Clin Cancer Res 7(12):4102-8; Schnitt S. J., 2001, J. Natl. Cancer Inst Monogr 30:22-6). In addition, the phenotypic and molecular characteristics of the tumor, especially histological grade, hormone receptor expression and HER2 amplification behave as both prognostic factors for relapse and death and predictive factors for responsiveness to hormone and cytotoxic therapy (Fitzgibbons et al., 1999, Arch. Pathol. Lab. Med. 124(7):966-78).
Evidence suggests that the immune response may also influence the progression of tumors. The concept of tumor immunosurveillance, proposed more than 40 years ago (Burnet, F. M., 1967, Lancet 1(7501):1171-4), was supported in humans by epidemiological studies revealing a correlation between clinical immunosuppression and cancer development (Keast, D., 1970, Lancet 2(7675):710-2). Tumor immunosurveillance was only recently demonstrated through the use of tumor-prone immuno-deficient mice (Smyth et al. 2001, Nat. Immunol. 2(4)293-9; Shankaran et al., 2001, Nature 410(6832):1107-11). Since then, the capacity of both the innate and the adaptive immune systems to affect the course of tumor development has been shown in several mouse models (Pardoll, D. M., 2001, Science 294(5542):534-6; Lanier, L. L., 2001, Nat. Med. 7(11):1178-80), and more recently in patients receiving a tumor-specific vaccine (Banchereau et al., 2001, Cell 106(3):271-4). However, the role of T-cell mediated immune response of clinically uncompromised patients in controlling the course of their tumors remains poorly documented.
The discovery and clinical validation of markers for cancer of all types which can predict prognosis and likelihood of invasive or metastatic spread is one of the major challenges facing oncology today. In breast cancer, 70% of the 186,000 annual cases present as lymph node negative; however, 30% of these cases will recur after local therapy (mastectomy or lumpectomy) (Boring et al., 1992, Clin. J. Cancer 42:19-38). Although adjuvant chemotherapy has been demonstrated to improve survival in node negative breast cancer patients (Mansour et al., 1989, Engl. J. Med. 485-490), it remains uncertain how to best identify patients whose risk of disease recurrence exceeds their risk of significant therapeutic toxicity (Osbourne, 1992, J. Clin. Oncol. 10:679-82).
In primary breast cancer, dendritic cells (DC) have been shown to infiltrate breast tumors (Bell et al., 1999, J. Exp Med. 190(10):1417-26) and antibodies directed against p53 (Lenner, et al., 1999, Br. J. Cancer 79(5-6):927-32) or HER2/neu (Disis et al., 1997, Adv. Cancer Res. 71:343-71) have been detected in patient serum. However, an efficient anti-tumor immune response has never been demonstrated. Indeed, in contrast with other tumor types, the incidence of breast cancer is rather reduced in immunocompromized patients (Stewart et al., 1995, Lancet 346(8978):796-8), and there has been one report to suggest that non-specific immunostimulating therapies may worsen the prognosis (Stewart et al., 1993, Clin. Exp. Metastasis 11(4):295-305). More recently, it has been shown that primary breast carcinoma are infiltrated with immature DC, leaving mature DC at the periphery of the tumor (Bell, et al., 1999, J. Exp. Med. 190(10):417-26; Suzuki, et al., 2002, J. Pathol. 196(1):37-43). However, the clinical relevance of this observation remains unclear, since immature DC infiltration in primary breast carcinoma does not seem to correlate with improved survival (Lewko et al., 2000, Med. Sci. Monit. 6(5):892-5; Lespagnard et al.,1999, Int. J. Cancer, 84(3):309-14) in contrast with other tumor types (Furukawa et al., 1985, Cancer, 56(11):2651-6; (Ambe et al., 1989, Cancer, 63(3):496-503; Gallo et al., 1991, Arch. Otolaryngol Head Neck Surg. 117(9):1007-10; Goldman et al.,1998, Arch. Otolaryngol Head Neck Surg. 124(6):641-6).
Plasmacytoid DC (pDC) are a DC subset characterized by their ultrastructural resemblance to Ig-secreting plasma cells upon isolation from tonsils (Grouard et al., 1997, J. Exp. Med. 185(6): 1101-1111), their unique surface phenotype (CD4+IL-3R++CD45RA+HLA-DR+) (Grouard et al., 1997, J. Exp. Med. 185(6):1101-1111; Facchetti et al., 1999, Histopathology 35(1):88-9; Res et al., 1999, Blood 94 (8):2647-57), and their ability to produce high levels of type I IFN and induce potent in vitro priming with either Th1, Th2 or even Ts polarization, depending on the activation conditions (Cella et al., 2000, Nat Immunol 1(4):305-10; Kadowaki et al., 2000, J Exp Med 192 (2):219-26). pDC are believed to be derived from a precursor common with T cells and B cells (Grouard et al., 1997, J. Exp. Med. 185, 6:1101-1111; Res et al., 1999, Blood 94, 8:2647-57; Bruno et al., 1997, J. Exp. Med. 185:875-884; Bendriss-Vermare et al., 2001, J.Cl. 107:835; Spits et al., 2000, J. Exp. Med. 192 (12):1775-84).
In addition to their morphology, their type I IFN production and their putative origin, pDC also differ from myeloid DC in their weak phagocytic activity (Grouard et al., 1997, J. Exp. Med. 185(6):1101-1111), their weak IL-12 production capacity (Rissoan et al., 1999, Science 283:1183-1186), and the signals inducing their activation (Kadowaki et al., 2001, J. Immunol 166(4):2291-5). While recruitment of activated pDC should initiate immunity through naive T cell activation, immature DC have been reported to induce immune tolerance, likely through induction of regulatory T cells (Jonuleit et al., 2001, Trends Immunol. 22:394; Bell et al., 2001, Trends Immunol. 22:11; Roncarolo et al., 2001, JEM 193:F5; Jonuleit et al., 2000, JEM 162:1213). Moreover, pDC have been shown to induce IL-10 secreting T cells (Rissoan et al., 1999, Science 283:1183; Liu et al., 2001, Nature Immunol. 2:585) and CD8 regulatory T cells (Gilliet et al.,2002, J. Exp. Med. 195(6):695-704). In addition, active recruitment of pDC in ovarian tumors has been reported (Curiel et al., 2001, Keystone Symposia Mar. 12-18, 2001: Dendritic Cells, Interfaces With Immunobiology and Medicine; Zou, et al., 2001, Nat Med, 7(12):1339-46), suggesting that pDC may be favorable to tumor development in certain circumstances, likely through induction of regulatory immune responses. In these cases, the tumor environment is suspected to prevent activation of pDC. Furthermore, increased number of pDC has been recently associated with auto-immune diseases, in particular with Lupus (Farkas et al., 2001, Am. J. Pathol. 159:237).
In regard to the continuing need for materials and methods useful in making clinical decisions on adjuvant therapy, markers of tumor immunosurveillance are attractive candidates whose prognosis value have to be statistically demonstrated.